Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or
metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation
and concomitant T790M mutation. Evidence of measurable or evaluable metastatic disease is
required.
Primary objective:
- To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response
rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M
mutation at diagnosis as defined by RECIST 1.1 criteria.
Secondary objectives:
- To determine the safety and tolerability profile of osimertinib (AZD9291), measured
using the number and severity of AEs entered into the Case Report Form (CRF); chemistry,
blood count, vital signs, physical examination, weight, ECG and performance status (S).
- To determine other efficacy parameters such as progression-free survival (PFS), overall
survival (OS), time to treatment failure (TTF), duration of response (DOR), disease
control rate (DCR), and tumor shrinkage (TS).
- To correlate the parameters of clinical response efficacy documented with the EGFR
mutational status.
- To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in
plasma and serum.
- To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to
EGFR TKI response and determine whether they are predictors of treatment response.
- To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the
site of covalent binding to the drug (C797) or other mutations in tissue or blood.
Type of study: Multicenter, international, single-arm, open-label, non-controlled phase IIa
clinical study.
Treatment: Patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os
(p.o.) daily.
Inclusion Criteria:
- Patient aged 18 years or older
- Patients with histological confirmation of locally advanced or metastatic,
non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and
concomitant T790M mutation who are not candidates for local curative treatment.
- Patients with a M1a stage according to the TNM version 7 including M1a (malignant
effusion) or M1b (distant metastasis), or locally advanced disease that is not a
candidate for curative treatment (including patients who progress after
chemoradiotherapy in stage III disease).
- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon
18 (G719X) and concomitant T790M mutation before treatment confirmed centrally.
- ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2.
- Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients
with asymptomatic and stable brain metastases are eligible for the study.
- Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection
of the primary tumor or metastatic tumor tissue, within the 60 days prior to study
entry.
- Life expectancy ≥12 weeks.
- Adequate hematologic function:
- Absolute neutrophil count (ANC) > 1.5 x 109/L
- platelet count > 100.0 x109/L
- hemoglobin > 9.0 g/dL (> 6.2 mmol/L).
- Adequate coagulation: INR ≤ 1.5.
- Adequate liver function
- Adequate renal function.
- Capacity to swallow, patient capable of completing treatment and accessible, ensuring
proper follow-up.
- Patients able to complete study and within geographical proximity allowing for
adequate follow-up.
- Resolution of all acute toxic effects of previous anti-cancer therapy (which can only
be adjuvant or neoadjuvant) or surgical interventions not exceeding grade ≤ 1
according to the NCI CTCAE version 4.0 (except for alopecia or other side effects that
the investigator does not consider to be a risk to patient safety).
- All men or women of childbearing potential must use a contraception method during the
study treatment and for at least 12 months after the last dose of the study drug.
- Signed and dated informed consent form
Exclusion Criteria:
- Locally advanced lung cancer candidate for curative treatment through radical surgery
and/or radio(chemo)therapy.
- Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with
predominantly squamous cell cancer, or with any small-cell lung cancer component.
- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon
18 (G719X) and concomitant T790M mutation before treatment that have not been
confirmed centrally.
- Patients who have received prior antineoplastic treatment for advanced disease.
- Second active neoplasia
- Patients with just one measurable or evaluable tumor lesion that has been resected or
irradiated prior to their enrollment in the study.
- Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation
pneumonitis requiring steroid treatment or any evidence of clinically active ILD.
- Corrected QT Interval (QTc) >470 msec, obtained from 3 ECGs at rest, using the QTc
value determined according to the clinical screening ECG machine.
- Any clinically significant abnormality in ECG rhythm, conduction or morphology at
rest.
- Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat
or sudden inexplicable death under the age of 40 in first-degree relatives or any
concomitant medications that prolong the QT interval.
- Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or
leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or
progressive neoplasia. Patients with history of CNS metastasis or compression of the
spinal cord are eligible if they have received local final treatment (e.g.,
radiotherapy, stereotactic surgery) and if they have remained clinically stable
without using anticonvulsants and corticosteroids for a minimum of 4 weeks prior to
the first day of study treatment.
- Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to
swallow study drug or significant intestinal resection that restricts the adequate
absorption of osimertinib (AZD9291).
- Patients who have had a surgical procedure unrelated to the study within 7 days prior
to the administration of the drug or a significant traumatic lesion during the 4 weeks
prior to starting the administration of the study drug, patients who have not
recovered from the side effects of any major surgery or patients who might need major
surgery during the course of the study.
- Pregnant or breastfeeding women. Women of childbearing potential, including women who
had their last menstrual period within the last two years, must have a negative serum
or urine pregnancy test in the 7 days prior to the start of the treatment.
- Patients who are not willing to use an adequate contraception method until 12 months
after the last dose of study treatment.
- Patients with a serious concomitant systemic disorder (e.g., active infection,
including HIV or heart disease) that is incompatible with the study (in the opinion of
the investigator), history of bleeding diathesis or anticoagulant therapy (the use of
low molecular weight heparin is permitted provided that it is used for prophylaxis).
- Patients with a history of cancer that has been completely treated, with no evidence
of malignant disease currently cannot be enrolled in the study if their chemotherapy
was completed less than 6 months prior and/or have received a bone marrow transplant
less than 2 years before the first day of study treatment.
- Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant
chemotherapy is permitted if at least 6 months have elapsed between the end of
chemotherapy and the first day of study treatment.
- Patients who have received prior EGFR treatments for lung cancer.
- Patients who have received treatment with an investigational drug within 3 weeks
before the first day of study treatment.
- Treatment with prohibited drugs within 14 days before the first day of study
treatment.
